Huntington's disease (HD) is a rare neurodegenerative genetic disorder that affects motor and cognitive functions, ultimately leading to dementia. In addition, although the disease is not itself fatal, it induces health complications (pneumonia, cardiac disorders) reducing the life expectancy of the person affected to about twenty years following the onset of symptoms.
It has been demonstrated that this disease is caused by a unique genetic mutation of the gene coding for the human Huntingtin protein (hHtt). This leads to synthesis of an abnormal protein, inducing neuronal disorders in the brain of the person affected by the disease.
FIG. 3 is a diagram of the gene of the human form of Huntingtin (hHtt). This gene contains 3144 amino acids. The N-terminal (N-term) fragment of this gene is shown in more detail. This N-term fragment contains 548 amino acids (including a domain rich in proline amino acids) as well as a polyglutamine (PolyQ) domain, of variable size, ranging from 0Q to 35Q for a normal protein. This polyQ domain corresponds to a sequence composed exclusively of glutamine amino acids (whose abbreviation to a corresponding letter is “Q”).
More specifically, in Huntington's disease, the abnormal protein is characterised by abnormal expansion of the polyQ domain contained in the N-terminal fragment of the hHtt protein.
When this domain exceeds 35Q, the polyQ-hHtt protein forms aggregates leading to degeneration of neurons in the striatum (a nervous structure responsible for motor function). Several studies have also identified an influence of the normal function of the Huntingtin protein in the disease.
To date, however, there is no effective treatment against this disease.
One treatment approach currently considered consists in fighting against aggregation of the polyQ domains in the protein, responsible for the disease.
A previous study (Mugat et al., Human Molecular Genetics, 2008) demonstrated a protective role of wild-type hHtt and its Drosophila homolog dHtt concerning aggregation of the polyQ-hHtt proteins. It was in fact possible to rescue the phenotypes induced by the polyQ-hHtt mutant protein with the 548 amino acid (aa) N-terminus (N-ter) fragment of hHtt or with the 620aa N-ter fragment of the Drosophila homolog of Htt (dHtt). These sequences are shown on FIGS. 1B and 1A respectively. FIG. 1B shows on the first line the series of glutamine amino acids (21Q in total) of this normal hHtt protein.
However, use of a protein of 548 and/or 620 amino acids could not reasonably be considered in the context of a genetic therapy. Indeed, in view of the numerous functions carried out by the huntingtin protein and in particular by its N-terminal end, these proteins would also be likely to carry out other functions whose type is not controlled.
The invention therefore relates to particularly targeted novel compounds that can be used as a drug to treat Huntington's disease.